Comparative resistance of idarubicin, doxorubicin and their C-13 alcohol metabolites in human MDR1 transfected NIH-3T3 cells.

Abstract

The anthracycline analog idarubicin (ID) is useful in the treatment of leukemias, and is of further interest because of the unique activity of its major circulating metabolite idarubicinol (IDOL). In vitro studies have shown that ID retains activity against tumor cells made resistant by prolonged exposure to substrates of the p-glycoprotein energy-dependent efflux pump. To selectively investigate multidrug resistance to ID in tumor cells, ID, IDOL, doxorubicin (DX) and doxorubicinol (DXOL) were evaluated for growth inhibitory activity when incubated with NIH-MDR1-G185 (MDR) cells or with the parent NIH-3T3 (3T3) cells. The MDR cells are transfected with the human multidrug gene mdr1, and express a functional p-glycoprotein. ID growth inhibitory activity was much less affected by p-glycoprotein-mediated efflux than was DX. ID IC50 values were only 1.8-fold greater in the MDR cell line than in the parental 3T3 cell line, while the IC50 value for DX was 12.3-fold greater in the transfected cell line. Verapamil (VRP) fully restored drug sensitivity of the MDR cell line to ID and DX. In studies with the alcohol metabolites, IDOL and DXOL IC50 values were 7.8- and 18.9-fold greater, respectively, for the MDR cell line than for the parental cell line. Intracellular concentrations of DX and DXOL, but not ID and IDOL, were substantially increased in the MDR cells when VRP was present in the incubation mixtures. ID and IDOL retain substantial growth inhibitory activity in mdr1-transfected cells, and ID may be of value in clinical settings where multidrug resistance mediated by p-glycoprotein is a potential limitation of therapy.

• Authors: M J Kuffel, M M Ames
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 36 Issue 3 Pg. 223-6 ( 1995) ISSN: 0344-5704 [Print] Germany
• PMID: 7781142 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Doxorubicin
• idarubicinol
• adriamycinol
• Idarubicin
• Daunorubicin

Topics

• 3T3 Cells
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis)
• Animals
• Antineoplastic Agents (toxicity)
• Biological Transport
• Cell Line (drug effects)
• Daunorubicin (analogs & derivatives, metabolism, toxicity)
• Doxorubicin (analogs & derivatives, metabolism, toxicity)
• Drug Resistance, Multiple (genetics)
• Humans
• Idarubicin (metabolism, toxicity)
• Mice
• Transfection